Meropenem, an ultra-broad spectrum injectable antibiotic used to treat a wide variety of infections, including meningitis and pneumonia, was first disclosed in U.S. Pat. No. 4,888,344. It is a beta-lactam antibiotic and belongs to the subgroup of carbapenem, similar to imipenem and ertapenem.
U.S. Pat. No. 4,888,344 provides a process for the preparation of the crystalline trihydrate of meropenem. U.S. Pat. Nos. 4,943,569 and 5,122,604 provide similar processes for the preparation of meropenem trihydrate. (4-Nitrobenzyl(4R,5S,6S)-(3-{(3S,5S)-5-[(dimethylamino)carbonyl]-1-[(4-nitrophenoxy)carbonxyl]pyrrolidin-3-yl}thio-6-[(1R)-1-hydorxyethyl]-4-methyl-7-oxo-1-azabicyclo[3.2.0].hept-2-ene-2-carboxylate) known as key intermediate of meropenem (Formula I) chemically known ((4R,5S,6S)-3-[[(3S,5S)-5-(Dimethylcarbamoyl)-3-pyrrolidinyl]thio]-6-[(1R)-1-hydroxy-ethyl]-4-methyl-7-oxo-1-azabicyclo[3.2.0]hept-2-ene-2-carboxylic acid)), Formula II which is synthetic broad spectrum, carbapenem antibiotic.
The compound of Formula I in non crystalline form e.g amorphous form, in form of oil, foamy solid generally is known with poor materials properties such as stability or purity and isolating properties compared to crystalline forms. In synthesis, the obtainment of product in crystalline form is necessary as the same is available with more purity. Moreover, the crystalline materials have substantially better stability than amorphous form.
WO2006/035300 A2 describes a process for preparing Meropenem by using biphasic solvent system for the deprotection of compound of Formula (V), which is similar to the teachings provided in U.S. Pat. No. 4,943,569, where ethyl acetate was added after the hydrogenation to remove organic impurity.
WO2006/035300A2 further claims a process for preparing Meropenem trihydrate in which the penultimate compound of Formula-V shown above was not isolated. This teaching is similar to the disclosure of U.S. Pat. No. 4,888,344, where, the suggestion has given to the extent that a Meropen trihydrate can be directly crystallized out from the resultant aqueous concentrate.WO2005/118586 A1 claims crystalline penultimate compound of Formula I and a process for preparing this intermediate. According to this publication, the intermediate is crystallized out either from concentrating the mother liquor in alkyl alkanoate such as ethyl acetate or by the addition of anti-solvent such as cyclohexane or heptane to the mother liquor in ethyl acetate. Since this publication describes the use of multiple solvent systems, the processes are not commercially viable from industrial point of view owing to multiple solvent recoveries, thus, adding further cost to the production.
As per U.S. Pat. No. 4,888,344 in example 1, Meropenem is dissolved in water, where upon small amount of meropenem crystals formed and further addition of acetone yielded meropenem trihydrate. Since the sterile preparation requires complete dissolution for sterile filtration, this technique is not found attractive.
According to the above mentioned patent literature, Meropenem trihydrate was obtained by subjecting the aqueous reaction mass after the deprotection of protecting group to hydrogenation at high pressure, and also to reverse osmosis (if necessary), followed by adding water-miscible organic solvent such as ethanol, iso-propanol, acetone, tetrahydrofuran (THF), dioxane, acetonitrile, etc.
In our embodiment, such a type of explosive step like hydrogenation at high pressure has been avoided to obtain meropenem trihydrate.
Therefore, there is need to provide a cost effective and eco-friendly process for preparation of meropenem trihydrate. Accordingly the present invention provides a process which devoid of the use of expensive and hazardous reagents and critical reaction parameters. Also, the solvent used as reaction medium is recovered to greater extent after the completion of reaction, which makes the process commercially applicable for industrial scale furthermore, the embodiment is deprotection reaction carried out at 6.5 to 6.9 pH of reaction mass by using the carbonate water or phosphate buffer or morpholine buffer of pH-7 so as to achieve maximum yield and good purity.